Molecular Neurobiology

, Volume 48, Issue 3, pp 769–782 | Cite as

Nitric Oxide and Zinc-Mediated Protein Assemblies Involved in Mu Opioid Receptor Signaling

  • María Rodríguez-MuñozEmail author
  • Javier Garzón


Opioids are among the most effective analgesics in controlling the perception of intense pain, although their continuous use decreases their potency due to the development of tolerance. The glutamate N-methyl-d-aspartate (NMDA) receptor system is currently considered to be the most relevant functional antagonist of morphine analgesia. In the postsynapse of different brain regions the C terminus of the mu-opioid receptor (MOR) associates with NR1 subunits of NMDARs, as well as with a series of signaling proteins, such as neural nitric oxide synthase (nNOS)/nitric oxide (NO), protein kinase C (PKC), calcium and calmodulin-dependent kinase II (CaMKII) and the mitogen-activated protein kinases (MAPKs). NO is implicated in redox signaling and PKC falls under the regulation of zinc metabolism, suggesting that these signaling elements might participate in the regulation of MOR activity by the NMDAR. In this review, we discuss the influence of redox signaling in the mechanisms whose plasticity triggers opioid tolerance. Thus, the MOR C terminus assembles a series of signaling proteins around the homodimeric histidine triad nucleotide-binding protein 1 (HINT1). The NMDAR NR1 subunit and the regulator of G protein signaling RGSZ2 bind HINT1 in a zinc-independent manner, with RGSZ2 associating with nNOS and regulating MOR-induced production of NO. This NO acts on the RGSZ2 zinc finger, providing the zinc ions that are required for PKC/Raf-1 cysteine-rich domains to simultaneously bind to the histidines present in the HINT1 homodimer. The MOR-induced activation of phospholipase β (PLCβ) regulates PKC, which increases the reactive oxygen species (ROS) by acting on NOX/NADPH, consolidating the long-term PKC activation required to regulate the Raf-1/MAPK cascade and enhancing NMDAR function. Thus, RGSZ2 serves as a Redox Zinc Switch that converts NO signals into Zinc signals, thereby modulating Redox Sensor Proteins like PKCγ and Raf-1. Accordingly, redox-dependent and independent processes weave together to situate the MOR under the negative control of the NMDAR.


Opioid signaling Redox signaling Mu opioid receptor Nitric oxide Zinc metabolism Glutamate NMDA receptor 



This research was supported by MSC “Plan Nacional sobre Drogas 2011-014” and “Ministerio de Economía y Competitividad (MINECO), SAF 2012-34991”.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material


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  1. 1.
    Huidobro F, Huidobro-Toro JP, Way EL (1976) Studies on tolerance development to single doses of morphine in mice. J Pharmacol Exp Ther 198:318–329PubMedGoogle Scholar
  2. 2.
    Kornetsky C, Bain G (1968) Morphine: single-dose tolerance. Science 162:101–102Google Scholar
  3. 3.
    Bilsky EJ, Bernstein RN, Wang Z, Sadee W, Porreca F (1996) Effects of naloxone and d-Phe-Cys-Tyr–d-Trp-Arg-Thr-Pen-Thr-NH2 and the protein kinase inhibitors H7 and H8 on acute morphine dependence and antinociceptive tolerance in mice. J Pharmacol Exp Ther 277:484–490PubMedGoogle Scholar
  4. 4.
    Huidobro-Toro JP, Way EL (1978) Single-dose tolerance to antinociception, and physical dependence on beta-endorphin in mice. Eur J Pharmacol 52:179–189PubMedGoogle Scholar
  5. 5.
    Fairbanks CA, Wilcox GL (1997) Acute tolerance to spinally administered morphine compares mechanistically with chronically induced morphine tolerance. J Pharmacol Exp Ther 282:1408–1417PubMedGoogle Scholar
  6. 6.
    Rodríguez-Muñoz M, de la Torre-Madrid E, Sánchez-Blázquez P, Garzón J (2007) Morphine induces endocytosis of neuronal m-opioid receptors through the sustained transfer of Ga subunits to RGSZ2 proteins. Mol Pain 3:19PubMedCentralPubMedGoogle Scholar
  7. 7.
    Rodríguez-Muñoz M, Sánchez-Blázquez P, Vicente-Sánchez A, Berrocoso E, Garzón J (2012) The mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control. Neuropsychopharmacology 37:338–349PubMedGoogle Scholar
  8. 8.
    Marie N, Aguila B, Allouche S (2006) Tracking the opioid receptors on the way of desensitization. Cell Signal 18:1815–1833PubMedGoogle Scholar
  9. 9.
    Wang ZJ, Wang LX (2006) Phosphorylation: a molecular switch in opioid tolerance. Life Sci 79:1681–1691PubMedGoogle Scholar
  10. 10.
    He L, Fong J, von Zastrow M, Whistler JL (2002) Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 108:271–282PubMedGoogle Scholar
  11. 11.
    Finn AK, Whistler JL (2001) Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron 32:829–839PubMedGoogle Scholar
  12. 12.
    Tsao P, von Zastrow M (2000) Downregulation of G protein-coupled receptors. Curr Opin Neurobiol 10:365–369PubMedGoogle Scholar
  13. 13.
    Rodríguez-Muñoz M, de la Torre-Madrid E, Gaitán G, Sánchez-Blázquez P, Garzón J (2007) RGS14 prevents morphine from internalizing mu-opioid receptors in periaqueductal gray neurons. Cell Signal 19:2558–2571PubMedGoogle Scholar
  14. 14.
    Garzón J, Rodríguez-Díaz M, De Antonio I, De Felipe J, Rodríguez JR, Sánchez-Blázquez P (1999) Myr+-Gi2a and Goa subunits restore the efficacy of opioids, clonidine and neurotensin giving rise to antinociception in G-protein knock-down mice. Neuropharmacology 38:1861–1873PubMedGoogle Scholar
  15. 15.
    Garzón J, Sánchez-Blázquez P (2001) Administration of myr+-Gi2a subunits prevents acute tolerance (tachyphylaxis) to mu-opioid effects in mice. Neuropharmacology 40:560–569PubMedGoogle Scholar
  16. 16.
    Maher CE, Martin TJ, Childers SR (2005) Mechanisms of mu opioid receptor/G-protein desensitization in brain by chronic heroin administration. Life Sci 77:1140–1154PubMedGoogle Scholar
  17. 17.
    Sim-Selley LJ, Selley DE, Vogt LJ, Childers SR, Martin TJ (2000) Chronic heroin self-administration desensitizes m opioid receptor-activated G-proteins in specific regions of rat brain. J Neurosci 20:4555–4562PubMedGoogle Scholar
  18. 18.
    Sim LJ, Selley DE, Dworkin SI, Childers SR (1996) Effects of chronic morphine administration on m opioid receptor-stimulated [35S]GTPgS autoradiography in rat brain. J Neurosci 16:2684–2692PubMedGoogle Scholar
  19. 19.
    Garzón J, Rodríguez-Díaz M, López-Fando A, Sánchez-Blázquez P (2001) RGS9 proteins facilitate acute tolerance to mu-opioid effects. Eur J Neurosci 13:801–811PubMedGoogle Scholar
  20. 20.
    Garzón J, Rodríguez-Díaz M, López-Fando A, García-España A, Sánchez-Blázquez P (2002) Glycosylated phosducin-like protein long regulates opioid receptor function in mouse brain. Neuropharmacology 42:813–828PubMedGoogle Scholar
  21. 21.
    Garzón J, Rodriguez-Muñoz M, de la Torre-Madrid E, Sánchez-Blázquez P (2005) Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS. Psychopharmacology (Berl) 180:1–11Google Scholar
  22. 22.
    Garzón J, Rodríguez-Muñoz M, López-Fando A, Sánchez-Blázquez P (2005) Activation of m-opioid receptors transfers control of Ga subunits to the regulator of G-protein signaling RGS9-2: role in receptor desensitization. J Biol Chem 280:8951–8960PubMedGoogle Scholar
  23. 23.
    Garzón J, Rodríguez-Muñoz M, López-Fando A, Sánchez-Blázquez P (2005) The RGSZ2 protein exists in a complex with m-opioid receptors and regulates the desensitizing capacity of Gz proteins. Neuropsychopharmacology 30:1632–1648PubMedGoogle Scholar
  24. 24.
    Ibi M, Matsuno K, Matsumoto M, Sasaki M, Nakagawa T, Katsuyama M et al (2011) Involvement of NOX1/NADPH oxidase in morphine-induced analgesia and tolerance. J Neurosci 31:18094–18103PubMedGoogle Scholar
  25. 25.
    Psifogeorgou K, Terzi D, Papachatzaki MM, Varidaki A, Ferguson D, Gold SJ et al (2011) A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia. J Neurosci 31:5617–5624PubMedGoogle Scholar
  26. 26.
    Sánchez-Blázquez P, Rodríguez-Muñoz M, Montero C, Garzón J (2005) RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: the role of activated Gaz subunits. Neuropharmacology 48:134–150PubMedGoogle Scholar
  27. 27.
    Garzón J, Rodriguez-Muñoz M, Sánchez-Blázquez P (2008) Do pharmacological approaches that prevent opioid tolerance target different elements in the same regulatory machinery? Curr Drug Abuse Rev 1:222–238PubMedGoogle Scholar
  28. 28.
    Garzón J, Rodríguez-Muñoz M, Sánchez-Blazquez P (2012) Direct association of mu-opioid and NMDA glutamate receptors supports their cross-regulation: molecular implications for opioid tolerance. Curr Drug Abuse Rev 5:199–226PubMedGoogle Scholar
  29. 29.
    Sánchez-Blázquez P, Rodríguez-Muñoz M, Bailón C, Garzón J (2012) GPCRs promote the release of zinc ions mediated by nNOS/NO and the redox transducer RGSZ2 protein. Antioxid Redox Signal 17:1163–1177Google Scholar
  30. 30.
    Lima CD, Klein MG, Hendrickson WA (1997) Structure-based analysis of catalysis and substrate definition in the HIT protein family. Science 278:286–290PubMedGoogle Scholar
  31. 31.
    Brenner C (2002) Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Biochemistry 41:9003–9014PubMedCentralPubMedGoogle Scholar
  32. 32.
    Pearson JD, DeWald DB, Mathews WR, Mozier NM, Zurcher-Neely HA, Heinrikson RL et al (1990) Amino acid sequence and characterization of a protein inhibitor of protein kinase C. J Biol Chem 265:4583–4591PubMedGoogle Scholar
  33. 33.
    McDonald JR, Groschel-Stewart U, Walsh MP (1987) Properties and distribution of the protein inhibitor (Mr 17,000) of protein kinase C. Biochem J 242:695–705PubMedGoogle Scholar
  34. 34.
    Martin J, St-Pierre MV, Dufour JF (2011) Hit proteins, mitochondria and cancer. Biochim Biophys Acta 1807:626–632PubMedGoogle Scholar
  35. 35.
    Huber O, Weiske J (2008) Beta-catenin takes a HIT1. Cell Cycle 7:1326–1331PubMedGoogle Scholar
  36. 36.
    Guang W, Wang H, Su T, Weinstein IB, Wang JB (2004) Role of mPKCI, a novel mu-opioid receptor interactive protein, in receptor desensitization, phosphorylation, and morphine-induced analgesia. Mol Pharmacol 66:1285–1292PubMedGoogle Scholar
  37. 37.
    Rodríguez-Muñoz M, Sánchez-Blázquez P, Vicente-Sánchez A, Bailón C, Martín-Aznar B, Garzón J (2011) The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor-glutamate NMDA receptor cross-regulation. Cell Mol Life Sci 68:2933–2949PubMedGoogle Scholar
  38. 38.
    Ajit SK, Ramineni S, Edris W, Hunt RA, Hum WT, Hepler JR et al (2007) RGSZ1 interacts with protein kinase C interacting protein PKCI-1 and modulates mu opioid receptor signaling. Cell Signal 19:723–730PubMedGoogle Scholar
  39. 39.
    Rodríguez-Muñoz M, Torre-Madrid E, Sánchez-Blázquez P, Wang JB, Garzón J (2008) NMDAR-nNOS generated zinc recruits PKCgamma to the HINT1–RGS17 complex bound to the C terminus of mu-opioid receptors. Cell Signal 20:1855–1864PubMedGoogle Scholar
  40. 40.
    Lima CD, Klein MG, Weinstein IB, Hendrickson WA (1996) Three-dimensional structure of human protein kinase C interacting protein 1, a member of the HIT family of proteins. Proc Natl Acad Sci U S A 93:5357–5362PubMedCentralPubMedGoogle Scholar
  41. 41.
    Bardaweel S, Pace J, Chou TF, Cody V, Wagner CR (2010) Probing the impact of the echinT C-terminal domain on structure and catalysis. J Mol Biol 404:627–638PubMedGoogle Scholar
  42. 42.
    Rodríguez-Muñoz M, Torre-Madrid E, Sánchez-Blázquez P, Garzón J (2011) NO-released zinc supports the simultaneous binding of Raf-1 and PKCgamma cysteine-rich domains to HINT1 protein at the mu-opioid receptor. Antioxid Redox Signal 14:2413–2425PubMedGoogle Scholar
  43. 43.
    Korichneva I, Hoyos B, Chua R, Levi E, Hammerling U (2002) Zinc release from protein kinase C as the common event during activation by lipid second messenger or reactive oxygen. J Biol Chem 277:44327–44331PubMedGoogle Scholar
  44. 44.
    Korichneva I (2006) Zinc dynamics in the myocardial redox signaling network. Antioxid Redox Signal 8:1707–1721PubMedGoogle Scholar
  45. 45.
    Hunt TW, Fields TA, Casey PJ, Peralta EG (1996) RGS10 is a selective activator of G alpha i GTPase activity. Nature 383:175–177PubMedGoogle Scholar
  46. 46.
    Berman DM, Kozasa T, Gilman AG (1996) The GTPase-activating protein RGS4 stabilizes the transition state for nucleotide hydrolysis. J Biol Chem 271:27209–27212PubMedGoogle Scholar
  47. 47.
    Mao H, Zhao Q, Daigle M, Ghahremani MH, Chidiac P, Albert PR (2004) RGS17/RGSZ2, a novel regulator of Gi/o, Gz, and Gq signaling. J Biol Chem 279:26314–26322PubMedGoogle Scholar
  48. 48.
    Garzón J, Rodríguez-Muñoz M, Vicente-Sánchez A, García-López MA, Martínez-Murillo R, Fischer T et al (2011) SUMO-SIM interactions regulate the activity of RGSZ2 proteins. PLoS One 6:e28557PubMedCentralPubMedGoogle Scholar
  49. 49.
    Garzón J, Rodríguez-Muñoz M, Vicente-Sánchez A, Bailón C, Martínez-Murillo R, Sánchez-Blázquez P (2011) RGSZ2 binds to the neural nitric oxide synthase PDZ domain to regulate mu-opioid receptor-mediated potentiation of the N-methyl-d-aspartate receptor-calmodulin-dependent protein kinase II pathway. Antioxid Redox Signal 15:873–887PubMedGoogle Scholar
  50. 50.
    Rodríguez-Muñoz M, Bermúdez D, Sánchez-Blázquez P, Garzón J (2007) Sumoylated RGS-Rz proteins act as scaffolds for Mu-opioid receptors and G-protein complexes in mouse brain. Neuropsychopharmacology 32:842–850PubMedGoogle Scholar
  51. 51.
    Wang J, Tu Y, Woodson J, Song X, Ross EM (1997) A GTPase-activating protein for the G protein Galphaz. Identification, purification, and mechanism of action. J Biol Chem 272:5732–5740PubMedGoogle Scholar
  52. 52.
    McConell GK, Bradley SJ, Stephens TJ, Canny BJ, Kingwell BA, Lee-Young RS (2007) Skeletal muscle nNOS mu protein content is increased by exercise training in humans. Am J Physiol Regul Integr Comp Physiol 293:R821–R828PubMedGoogle Scholar
  53. 53.
    Rothe F, Langnaese K, Wolf G (2005) New aspects of the location of neuronal nitric oxide synthase in the skeletal muscle: a light and electron microscopic study. Nitric Oxide 13:21–35PubMedGoogle Scholar
  54. 54.
    Schwarz PM, Kleinert H, Forstermann U (1999) Potential functional significance of brain-type and muscle-type nitric oxide synthase I expressed in adventitia and media of rat aorta. Arterioscler Thromb Vasc Biol 19:2584–2590PubMedGoogle Scholar
  55. 55.
    Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC (1999) Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci U S A 96:657–662PubMedCentralPubMedGoogle Scholar
  56. 56.
    Stamler JS, Meissner G (2001) Physiology of nitric oxide in skeletal muscle. Physiol Rev 81:209–237PubMedGoogle Scholar
  57. 57.
    Lau KS, Grange RW, Isotani E, Sarelius IH, Kamm KE, Huang PL et al (2000) nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol Genomics 2:21–27PubMedGoogle Scholar
  58. 58.
    Santizo R, Baughman VL, Pelligrino DA (2000) Relative contributions from neuronal and endothelial nitric oxide synthases to regional cerebral blood flow changes during forebrain ischemia in rats. Neuroreport 11:1549–1553PubMedGoogle Scholar
  59. 59.
    Boissel JP, Schwarz PM, Forstermann U (1998) Neuronal-type NO synthase: transcript diversity and expressional regulation. Nitric Oxide 2:337–349PubMedGoogle Scholar
  60. 60.
    Reif A, Frohlich LG, Kotsonis P, Frey A, Bommel HM, Wink DA et al (1999) Tetrahydrobiopterin inhibits monomerization and is consumed during catalysis in neuronal NO synthase. J Biol Chem 274:24921–24929PubMedGoogle Scholar
  61. 61.
    Sagami I, Daff S, Shimizu T (2001) Intra-subunit and inter-subunit electron transfer in neuronal nitric-oxide synthase: effect of calmodulin on heterodimer catalysis. J Biol Chem 276:30036–30042PubMedGoogle Scholar
  62. 62.
    Noguchi T, Sagami I, Daff S, Shimizu T (2001) Important role of tetrahydrobiopterin in no complex formation and interdomain electron transfer in neuronal nitric-oxide synthase. Biochem Biophys Res Commun 282:1092–1097PubMedGoogle Scholar
  63. 63.
    Hemmens B, Goessler W, Schmidt K, Mayer B (2000) Role of bound zinc in dimer stabilization but not enzyme activity of neuronal nitric-oxide synthase. J Biol Chem 275:35786–35791PubMedGoogle Scholar
  64. 64.
    Roman LJ, Masters BS (2006) Electron transfer by neuronal nitric-oxide synthase is regulated by concerted interaction of calmodulin and two intrinsic regulatory elements. J Biol Chem 281:23111–23118PubMedGoogle Scholar
  65. 65.
    Sánchez-Blázquez P, Rodríguez-Muñoz M, Garzón J (2010) Mu-opioid receptors transiently activate the Akt–nNOS pathway to produce sustained potentiation of PKC-mediated NMDAR–CaMKII signaling. PLoS One 5:e11278PubMedCentralPubMedGoogle Scholar
  66. 66.
    Chen L, Huang LY (1991) Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a m opioid. Neuron 7:319–326PubMedGoogle Scholar
  67. 67.
    Lu WY, Xiong ZG, Lei S, Orser BA, Dudek E, Browning MD et al (1999) G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat Neurosci 2:331–338PubMedGoogle Scholar
  68. 68.
    Ali DW, Salter MW (2001) NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity. Curr Opin Neurobiol 11:336–342PubMedGoogle Scholar
  69. 69.
    Salter MW, Kalia LV (2004) Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 5:317–328PubMedGoogle Scholar
  70. 70.
    Ma YC, Huang J, Ali S, Lowry W, Huang XY (2000) Src tyrosine kinase is a novel direct effector of G proteins. Cell 102:635–646PubMedGoogle Scholar
  71. 71.
    Thornton C, Yaka R, Dinh S, Ron D (2003) H-Ras modulates N-methyl-d-aspartate receptor function via inhibition of Src tyrosine kinase activity. J Biol Chem 278:23823–23829PubMedCentralPubMedGoogle Scholar
  72. 72.
    Sánchez-Blázquez P, Rodríguez-Muñoz M, de la Torre-Madrid E, Garzón J (2009) Brain-specific Gaz interacts with Src tyrosine kinase to regulate Mu-opioid receptor-NMDAR signaling pathway. Cell Signal 21:1444–1454PubMedGoogle Scholar
  73. 73.
    Chakravarthy B, Morley P, Whitfield J (1999) Ca2+-calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains. Trends Neurosci 22:12–16PubMedGoogle Scholar
  74. 74.
    Trujillo KA (2002) The neurobiology of opiate tolerance, dependence and sensitization: mechanisms of NMDA receptor-dependent synaptic plasticity. Neurotox Res 4:373–391PubMedGoogle Scholar
  75. 75.
    Glass MJ, Vanyo L, Quimson L, Pickel VM (2009) Ultrastructural relationship between N-methyl-d-aspartate-NR1 receptor subunit and mu-opioid receptor in the mouse central nucleus of the amygdala. Neuroscience 163:857–867PubMedCentralPubMedGoogle Scholar
  76. 76.
    Commons KG, van Bockstaele EJ, Pfaff DW (1999) Frequent colocalization of mu opioid and NMDA-type glutamate receptors at postsynaptic sites in periaqueductal gray neurons. J Comp Neurol 408:549–559PubMedGoogle Scholar
  77. 77.
    Narita M, Hashimoto K, Amano T, Narita M, Niikura K, Nakamura A et al (2008) Post-synaptic action of morphine on glutamatergic neuronal transmission related to the descending antinociceptive pathway in the rat thalamus. J Neurochem 104:469–478PubMedGoogle Scholar
  78. 78.
    Mori H, Mishina M (1995) Structure and function of the NMDA receptor channel. Neuropharmacology 34:1219–1237PubMedGoogle Scholar
  79. 79.
    Zukin RS, Bennett MV (1995) Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci 18:306–313PubMedGoogle Scholar
  80. 80.
    Maret W, Vallee BL (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc Natl Acad Sci U S A 95:3478–3482PubMedCentralPubMedGoogle Scholar
  81. 81.
    Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118PubMedGoogle Scholar
  82. 82.
    Maret W (2009) Molecular aspects of human cellular zinc homeostasis: redox control of zinc potentials and zinc signals. Biometals 22:149–157PubMedGoogle Scholar
  83. 83.
    Colvin RA, Holmes WR, Fontaine CP, Maret W (2010) Cytosolic zinc buffering and muffling: their role in intracellular zinc homeostasis. Metallomics 2:306–317PubMedGoogle Scholar
  84. 84.
    Bitanihirwe BK, Cunningham MG (2009) Zinc: the brain's dark horse. Synapse 63:1029–1049PubMedGoogle Scholar
  85. 85.
    Maret W (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal 8:1419–1441PubMedGoogle Scholar
  86. 86.
    Shahani N, Sawa A (2011) Nitric oxide signaling and nitrosative stress in neurons: role for S-nitrosylation. Antioxid Redox Signal 14:1493–1504PubMedGoogle Scholar
  87. 87.
    Maret W (2000) The function of zinc metallothionein: a link between cellular zinc and redox state. J Nutr 130:1455S–1458SPubMedGoogle Scholar
  88. 88.
    Ilbert M, Graf PC, Jakob U (2006) Zinc center as redox switch—new function for an old motif. Antioxid Redox Signal 8:835–846PubMedGoogle Scholar
  89. 89.
    Palumaa P (2009) Biological redox switches. Antioxid Redox Signal 11:981–983PubMedGoogle Scholar
  90. 90.
    Newton AC (2001) Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101:2353–2364PubMedGoogle Scholar
  91. 91.
    Zhao F, Ilbert M, Varadan R, Cremers CM, Hoyos B, Acin-Perez R et al (2011) Are zinc-finger domains of protein kinase C dynamic structures that unfold by lipid or redox activation? Antioxid Redox Signal 14:757–766PubMedGoogle Scholar
  92. 92.
    Knapp LT, Klann E (2000) Superoxide-induced stimulation of protein kinase C via thiol modification and modulation of zinc content. J Biol Chem 275:24136–24145PubMedGoogle Scholar
  93. 93.
    Tsui J, Inagaki M, Schulman H (2005) Calcium/calmodulin-dependent protein kinase II (CaMKII) localization acts in concert with substrate targeting to create spatial restriction for phosphorylation. J Biol Chem 280:9210–9216PubMedGoogle Scholar
  94. 94.
    Faux MC, Scott JD (1997) Regulation of the AKAP79–protein kinase C interaction by Ca2+/Calmodulin. J Biol Chem 272:17038–17044PubMedGoogle Scholar
  95. 95.
    Rameau GA, Chiu LY, Ziff EB (2004) Bidirectional regulation of neuronal nitric-oxide synthase phosphorylation at serine 847 by the N-methyl-d-aspartate receptor. J Biol Chem 279:14307–14314PubMedGoogle Scholar
  96. 96.
    Kroncke KD, Klotz LO (2009) Zinc fingers as biologic redox switches? Antioxid Redox Signal 11:1015–1027PubMedGoogle Scholar
  97. 97.
    Kalia LV, Salter MW (2003) Interactions between Src family protein tyrosine kinases and PSD-95. Neuropharmacology 45:720–728PubMedGoogle Scholar
  98. 98.
    Kalia LV, Pitcher GM, Pelkey KA, Salter MW (2006) PSD-95 is a negative regulator of the tyrosine kinase Src in the NMDA receptor complex. EMBO J 25:4971–4982PubMedGoogle Scholar
  99. 99.
    Koch T, Kroslak T, Mayer P, Raulf E, Höllt V (1997) Site mutation in the rat mu-opioid receptor demonstrates the involvement of calcium/calmodulin-dependent protein kinase II in agonist-mediated desensitization. J Neurochem 69:1767–1770PubMedGoogle Scholar
  100. 100.
    Chen Y, Sommer C (2009) The role of mitogen-activated protein kinase (MAPK) in morphine tolerance and dependence. Mol Neurobiol 40:101–107PubMedGoogle Scholar
  101. 101.
    Polakiewicz RD, Schieferl SM, Dorner LF, Kansra V, Comb MJ (1998) A mitogen-activated protein kinase pathway is required for mu-opioid receptor desensitization. J Biol Chem 273:12402–12406PubMedGoogle Scholar
  102. 102.
    Hoyos B, Imam A, Chua R, Swenson C, Tong GX, Levi E et al (2000) The cysteine-rich regions of the regulatory domains of Raf and protein kinase C as retinoid receptors. J Exp Med 192:835–845PubMedCentralPubMedGoogle Scholar
  103. 103.
    Doyle T, Bryant L, Muscoli C, Cuzzocrea S, Esposito E, Chen Z et al (2010) Spinal NADPH oxidase is a source of superoxide in the development of morphine-induced hyperalgesia and antinociceptive tolerance. Neurosci Lett 483:85–89PubMedCentralPubMedGoogle Scholar
  104. 104.
    Bokoch GM, Diebold B, Kim JS, Gianni D (2009) Emerging evidence for the importance of phosphorylation in the regulation of NADPH oxidases. Antioxid Redox Signal 11:2429–2441PubMedGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Neuropharmacology, Cajal InstituteMadridSpain
  2. 2.Instituto CajalMadridSpain

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